Hepatitis C virus (HCV) chronically infects 2-3% of the global population, predisposing the patients to chronic liver diseases and liver cancer. To combat this major public health threat, a detailed understanding of the viral molecules will greatly facilitate vaccine and anti-viral drug design. The HCV envelope glycoproteins (Env), comprised of heterodimers of the E1 and E2 viral glycoproteins, are important for viral attachment and entry into host cells, and the assembly of infectious virus particles. The E1 and E2 glycoproteins are potential targets for pharmacological and immunological intervention. The goals of this application are to determine the high-resolution crystal structure of HCV envelope glycoproteins, and the functions of the glycoproteins at the amino acid level. The results will aid the rational design of anti-viral drugs and vaccines, and to understand the viral entry mechanism. The specific aims are (i) to determine the high-resolution crystal structure of HCV E2 and E2:receptor complex; (ii) to study the roles of individual amino acid residues in protein functions by a shotgun mutagenesis approach; and (iii) to determine the high-resolution crystal structures of HCV E1 and E1E2 complex.